The TH2 cytokines, interleukins-4 and -13 (IL4 & IL13), are important determinants of immune system activation and polarity. In addition to T cell stimulation, these cytokines are drivers of the 'M2' pro-tumorigenic macrophage phenotype. Additionally, both cytokines can bind a heterodimeric receptor found on tumor cells of several types. Our goal is to to define the function of IL4/IL13 signaling in tumor behavior and determine if this pathway represents a therapeutic target, particularly for metastatic cancers. We have used stable knockdown of il4ra, the signaling competent component of the heterodimeric IL4/IL13 receptor, in human and murine mammary and colon tumor cell lines to assess the contributions of IL4 and IL13 signaling to proliferation, survival and invasion of tumor cells in vitro. These lines were also implanted in vivo. Additionally, de novo carcinogenesis studies in il4ra- deficient mice were performed. Finally, we did a pilot study with an IL4 neutralizing agent to test therapeutic potential. Expression of il4ra was reduced by 50-90% in the murine colon tumor lines MC38 and CT26 and mammary lines 4T1 and PyvT-R221A. Knockdown clones grew more slowly than controls, but EdU assays failed to detect any differences in DNA synthesis amongst clones. MTT assays as well as direct cell counting indicated fewer cells over time, and this was corroborated by clonogenic assays which showed fewer and smaller colonies with knockdown lines compared to controls. These effects were most likely due to a difference in basal survival. When cell lines were injected in vivo, either orthotopically or intravenously or intrasplenically for experimental metastases, significant attenuation of tumor growth was observed. Cecal tumors indicated effects on proliferation as determined by immunostaining for phosphohistone H3, with marginal effects on apoptosis. Il4ra-null mice, when exposed to azoxymethane and dextran sulfate sodium, developed fewer and smaller colonic tumors compared to wild type controls. Further, these tumors were less progressed as assessed by nuclear beta-catenin. In addition to reduced tumorigenicity when il4ra was genetically ablated, treatment of mice with an il4-neutralizing antibody also led to reduced tumor burden. Tumor cell IL4 receptor appears to be a strong survival factor for breast and colon tumors, impacting both primary tumor progression and metastatic growth. Therapeutic approaches targeting IL4/IL13 should be considered for metastatic carcinomas